Goralatide

Summary

Goralatide, also known as Ac‑SDKP, is a synthetic tetrapeptide that mimics the natural regulator acetyl‑Ser‑Asp‑Lys‑Pro. It selectively inhibits the proliferation of primitive haematopoietic stem and progenitor cells. Investigated mainly in pre‑clinical models, it has been used to protect normal bone‑marrow cells during hyperthermic purging and chemotherapy, and to explore antileukaemic activity of more stable analogues. The compound remains investigational and is not approved for therapeutic use.

Mechanism of Action

Ac‑SDKP functions as a physiological inhibitor of early haematopoietic cell cycling. It binds to yet‑undefined receptors on primitive progenitors, triggering signaling pathways that halt entry into S‑phase. The peptide is a preferred substrate of angiotensin‑I‑converting enzyme (ACE); degradation by ACE terminates its activity, linking the renin‑angiotensin and kallikrein‑kinin systems to stem‑cell regulation. By transiently suppressing normal progenitor proliferation, Goralatide reduces their sensitivity to stressors such as heat or cytotoxic drugs, while leukaemic precursors, which are less responsive, continue to be targeted.

What the Research Shows

Pre‑clinical work has shown that native Goralatide is rapidly degraded (half‑life ≈4.5 min) but that chemical analogues with aminoxy or other modifications retain activity and gain stability in solution. In murine models, pretreatment with Goralatide before a 90‑minute hyperthermic purge (43 °C) protected normal colony‑forming unit‑granulocyte‑macrophage (CFU‑GM) progenitors, reducing heat‑induced kill from 2‑log to about 1‑log, while leukaemic stem cells remained highly susceptible, thereby widening the therapeutic window. In mice receiving a myelotoxic dose of 5‑fluorouracil, repeated Goralatide injections preserved high‑proliferative‑potential colony‑forming cells in bone marrow, likely by modulating plasma factors that target the marrow. A double‑blind, randomized trial in 84 patients with head‑neck or oesophageal squamous‑cell carcinoma receiving carboplatin‑5‑FU found no significant improvement in nadir blood counts; anemia and lymphopenia were modestly more frequent in the Goralatide arms, although overall tolerability was reported as excellent. No regulatory approval has been granted.

Reported Benefits

Goralatide has demonstrated, in animal studies, the ability to shield normal haematopoietic progenitors from heat‑induced damage and from chemotherapy‑induced depletion, potentially improving bone‑marrow recovery. Stable analogues have shown cytotoxic activity against various leukaemia and tumour cell lines, suggesting a dual role as a protective agent and as a lead for antineoplastic drug development.

Limitations of the Evidence

Key limitations include the peptide’s extreme instability in biological fluids, rapid ACE‑mediated degradation, and a lack of consistent clinical efficacy. The sole human trial reported no hematologic advantage and a slight increase in anemia and lymphopenia. Findings are largely confined to rodent models, and dosing regimens that achieve protective plasma levels without off‑target effects remain undefined.

Safety Considerations

Available safety information is sparse. In the randomized cancer trial, Goralatide was well tolerated overall, but patients experienced a higher incidence of anemia and lymphopenia compared with placebo. No serious adverse events were attributed directly to the peptide in pre‑clinical studies. Because the molecule is rapidly degraded, systemic exposure is brief, yet caution is warranted when combining with myelosuppressive therapies.

How It Is Administered

Goralatide is administered by injection, typically intravenously or subcutaneously, in experimental protocols preceding hyperthermic purging or chemotherapy (e.g., 24 h before to 36 h after a 5‑FU dose). Formulations described in the literature are simple peptide solutions; no commercial drug product exists.

Routes of Administration

Goals & Uses

• Reduction of cardiac fibrosisAntifibroticLow
• Myeloprotection during chemotherapyHematopoietic ProtectionModerate
• Reduction of renal fibrosisAntifibroticLow
• Radioprotection of bone marrowRadioprotectionModerate

Contraindications

• Hypersensitivity to goralatide or excipientsAllergyHigh

Adverse Effects

• Injection site reactionsLocalUncommon
• Transient myelosuppression risk if dosed incorrectlyHematologicRare

Drug Interactions

• Cytotoxic chemotherapy agentsLow
• ACE inhibitorsModerate

Population Constraints

• PregnancyReproductive SafetyRelative
• Pediatric populationsAgeRelative

Regulatory Status

• European UnionInvestigationalNo EMA approval. Subject of academic and preclinical research.
• United StatesInvestigationalNo FDA approval. Investigated in clinical trials as a myeloprotective agent.
• United KingdomUnknownNo known MHRA approval or regulatory submission identified.

Not approved by FDA, EMA, or MHRA. Investigated in clinical and preclinical settings primarily as a myeloprotective agent and antifibrotic compound. No approved therapeutic indication as of the available data.

Evidence & Sources

• Synthesis and bioactivity of a Goralatide analog with antileukemic activity
  Journal ArticleLowLi Z, et al.2015-01-01T00:00:00.000000Z
• Reduction of heat-induced haemotoxicity in a hyperthermic purging protocol of murine acute myeloid leukaemic stem cells by AcSDKP
  Journal ArticleLowWierenga PK, Dillingh JH, Konings AW1997-01-01T00:00:00.000000Z
• [Randomized placebo trial of myeloprotection with goralatide in patients with squamous cell carcinoma of the upper respiratory and digestive tracts or esophagus, treated with a carboplatin-fluorouracil combination]
  Journal ArticleModerateCappelaere P, et al.1995-01-01T00:00:00.000000Z
• Synthesis of L-Lys-Aminoxy-Goralatide
  Journal ArticleLowLi Z, et al.2014-01-01T00:00:00.000000Z
• Angiotensin I-converting enzyme and potential substrates in human testis and testicular tumours
  Journal ArticleModerateFranke FE, et al.2003-01-01T00:00:00.000000Z
• In vivo modifications of AcSDKP metabolism and haematopoiesis in mice treated with 5-fluorouracil and Goralatide
  Journal ArticleLowComte L, et al.1998-01-01T00:00:00.000000Z

Frequently Asked Questions